Introduction: ‘Nagakesara’ aka ‘Cobra’s saffron’ is recommended in many ayurvedic remedies, consisting of dried stamens of Mesua ferrea Linn (Fam. Calophyllaceae). Thus, we aimed to develop a comprehensive quality control toolkit for M. ferrea stamen to ensure its identity, purity, consistency and mitigate adulteration. Materials and Methods: Collection, authentication, and pulverization of the stamens of M. ferrea was done for the determination of the physiochemical, qualitative and quantitative phytochemicals, HPLC and LC-MS fingerprint, as well as secondary-metabolites in the stamen extract in view of World Health Organization (WHO) and Indian Herbal Pharmacopoeia. Results: Collected stamens of M. ferrea were authenticated by the Botanical Survey of India. Determined physicochemical attributes of the authenticated powdered stamens were found within the permissible limits. Yield of the hydroalcoholic extract of the stamens was found to 18.26 % w/w and was found enriched in secondary metabolites viz., alkaloids, glycosides, coumarin, phenols, tannins, flavonoids, terpenoids, saponins, carbohydrates, phytosterols and amino acids. Quantified total phenolic, flavonoid and carbohydrate content were found to be 284.24 ± 8.18 μg equivalent of gallic acid/ mg, 242.52 ± 8.36 μg equivalent of quercetin/ mg and 92.34 ± 2.58 μg equivalent of glucose/ mg of extract, respectively, Further, HPTLC and LC-MS fingerprint profile of the extract were developed. Twenty phytochemicals were identified by the generated LC-MS data. Discussion: Established physicochemical, qualitative and quantitative phytochemical, chromatographic fingerprints and identified phytochemical profile of the M. ferrea stamens would serve as definitive tools for quality control and assurance measures by the regulatory authorities.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC50 values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625-250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.

A new series of substituted 1,3,4-thiadiazole-1,3,5-triazine hybrids was rationally designed, synthesized, and evaluated for their antiviral and antibacterial potential. The target di-substituted (9a-e) and tri-substituted (11a-e) derivatives were obtained via a stepwise nucleophilic substitution strategy from cyanuric chloride and characterized by spectroscopic techniques. Molecular docking studies against human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) revealed that para-substituted analogs displayed superior binding within the non-nucleoside reverse transcriptase inhibitor pocket through key hydrogen bonding, π-π stacking, and electrostatic interactions. In vitro evaluation identified compounds 11a as the most active candidate. Compound 11a exhibited 83.93% inhibition of RT activity at 1 μM, an EC50 of 72.7 nM, and effective suppression of HIV-1 replication in CEM-GFP T cells (85.19% p24 inhibition) with a favorable therapeutic index (TI = 471). Both compounds also demonstrated inhibition of SARS-CoV-2-induced cytopathic effects in Vero E6 cells at noncytotoxic concentrations. In addition, several derivatives showed moderate to good antibacterial activity against tested bacterial strains, with SAR analysis highlighting the importance of substituent electronics and positional effects on bioactivity. Overall, this study establishes substituted 1,3,4-thiadiazole-1,3,5-triazine hybrids as promising multifunctional scaffolds for antiviral and antibacterial drug development.

A series of novel 1,3,5-triazine-isonicotinamide derivatives were designed, synthesized, and evaluated in vitro as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for Alzheimer's disease (AD). A chemical library of 138 derivatives was constructed and screened using computer-aided tools to identify druglike molecular properties and non-toxic characteristics. In silico molecular docking studies targeting the active sites of AChE (PDB ID: 1EVE) and BChE (PDB ID: 4TPK) were then performed to select compounds for synthesis, followed by in vitro AChE and BChE assays. The selected compounds were synthesized using both conventional and microwave-assisted synthetic procedures, and their structures were confirmed using spectroscopic techniques, including FTIR, 1H NMR, 13C NMR, and mass spectrometry. The compound DZ98 was found to be the most potent, with log(IC50 [& micro;g/mL]) values of 1.11 against AChE and 1.72 against BChE, comparable to the standard drug Donepezil, which showed values of 0.50 and 0.91, respectively. Additionally, DZ98 displayed binding energies of -299.55 kcal/mol against AChE and -301.44 kcal/mol against BChE, with potential hydrogen-bonding as well as pi-pi, pi-cation, and pi-anion interactions with key amino acid residues at the active sites. This finding indicates that the incorporation of a nitro group in DZ98 may enhance hydrogen bonding within the catalytic site, resulting in enhanced inhibitory activity. Thus, the present study demonstrates that DZ98 may serve as a promising lead for AD as an AChE and BChE inhibitor.

The present study used a structurally directed pharmacophore hybridization technique to combine two important scaffolds, coumarin and thiazoles, in the search for novel class of a AChE and BuChE inhibitors for beneficial for Alzheimer's disease. A total of 120 compounds have been designed in two series using various substituted phenols, (3-ketoesters, and thiazole derivatives 5a(1-15), 5b(16-30), 5c(31-45), 5d(46-60), and 6a(61-75), 6b (76-90), 6c(91-105), 6d(106-120). Employing molecular property screening and docking, eight N-substituted thiazole benzamide-coumarin derivatives were found as potential candidates. Docking analysis revealed that compound 5b18 exhibited strong binding interactions with key amino acid residues ARG289,ASP72,TRP84 and TYR334 along with the binding energy 32.34 kcal/mol and GLY197,ASN289,TRP82 and ALA328 along with the binding energy 23.34 kcal/mol against acetylcholinesterase (1EVE) and butyrylcholinesterase (1P0I).Furthermore, this title compound was synthesized using conventional methods and characterized by various spectroscopic techniques. In vitro anti-cholinesterase assays demonstrated that compound 5b18 exhibited potent to moderate inhibitory activity against AChE and BuChE, with IC50 values ranging from 9.84 + 0.16 to 2.07+0.08 mu M mL- 1 for AChE and BuChE. Our study presents the development of a new class of hybrid coumarin-thiazole derivatives as AChE and BuChE inhibitors, suggesting their potential application in Alzheimer's disease treatment.

This study presents the design, synthesis, and biological evaluation of novel 1,3,5-triazine-morpholino-thiazine hybrids. These compounds were assessed for their in vitro inhibitory activity against DPP-4,-8, and-9, demonstrating a broad spectrum of inhibition against DPP-4 while exhibiting minimal or no activity against DPP- 8 and DPP-9. Among them, compound 8c emerged as the most potent DPP-4 inhibitor (IC50 = 3.2 nM), surpassing the standard inhibitor, Alogliptin. Molecular docking studies revealed that compound 8c exhibited the strongest binding affinity within the DPP-4 active site, interacting with key residues Lys554, Val546, and Tyr547. To further investigate its stability and interaction dynamics, a molecular dynamics simulation of compound 8c in complex with DPP-4 was performed using GROMACS. Simulations were conducted for both ligand-bound and unbound states, employing the CHARMM36-mar2019.ff force field for protein topology generation and SwissParam for ligand topology. Additionally, compound 8c demonstrated significant free radical scavenging activity in DPPH and H2O2 assays. Its in-vivo antidiabetic potential was evaluated in Wistar rats using a high-fat diet with a low-dose streptozotocin model. During the course of treatment, compound 8c effectively reduced blood glucose levels and body weight. It also improved lipid profiles by increasing HDL levels while decreasing LDL, TG, VLDL, and total cholesterol. Furthermore, oxidative stress markers, including CAT, GPx, GSH, and SOD, were significantly restored in kidney and liver tissues. Histopathological analysis via H&E staining indicated a dose- dependent improvement in the cellular architecture of liver, kidney, and pancreatic tissues. Finally, an in-silico ADME-T analysis was conducted to assess the pharmacokinetic properties and safety profile of the synthesized compounds. Collectively, these findings highlight the potential of 1,3,5-triazine-morpholino-thiazine hybrids, particularly compound 8c, as promising DPP-4 inhibitors with strong antidiabetic and antioxidant properties.

The development of resistance to antimalarial drugs such as chloroquine, amodiaquine, artemisinin, and antifolates is a major health concern, prompting more research into new antimalarial therapies. In the present study, we intend to develop pyrazole substituted 1,3,5-triazine derivatives 7(a-j) as antimalarial agents. These compounds were synthesized using conventional methods and analyzed using various spectroscopic techniques. The docking results showed that compounds 7j and 7i exhibited an excellent binding interactions with PRO A:113, ILE A:164, SER A:111, PHE A:58, LEU A:46, LEU A:119, VAL A:45, ILE A:112 (-204.97to -118.41 kcal/mol) and TYR A:170, CYS A:15, PRO A:113, ILE A:112, ALA A:16, PHE A:58, MET A:55, SER A:111 (-216.24to -152.06 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR-TS. Compounds 7j and 7i exhibited considerable antimalarial efficacy against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum, with IC50 values ranging from 23.78 to 83.36 μM and 30.89-64.24 μM, respectively. These pyrazole-substituted 1,3,5-triazine derivatives could be utilized to find a novel class of Pf-DHFR-TS inhibitors.

OBJECTIVES:To evaluate the antidepressant-like effects of Phenylthiazolyl-1,3,5-triazine derivatives through behavioral tests, molecular docking, and histopathological analysis in a rat brain model of depression. METHODS:Phenylthiazolyl-1,3,5-triazine derivatives were synthesized and administered at a dose of 30 mg/kg in albino rats. Behavioral effects were assessed using the Forced Swim Test and Tail Suspension Test. Molecular docking with MD simulations via CDocker was employed to analyze ligand-receptor interactions. Histological analysis of brain tissues was conducted to assess structural and vascular changes. RESULTS:Among the derivatives, PS1 and PS5 showed significant antidepressant-like activity compared to standard imipramine. Molecular docking revealed that hydrogen bonding, pi-pi interactions, and intermolecular neighbor effects stabilized the ligand-receptor complexes. Histopathological analysis of PS1-treated rats demonstrated preserved vascular integrity, reduced edema, and the absence of hydrophobic alterations. CONCLUSIONS:Phenylthiazolyl-1,3,5-triazines, particularly PS1, exhibit promising potential as antidepressant agents. Their behavioral efficacy and protective histological effects suggest therapeutic relevance. Further studies integrating biomarkers and gene expression analyses are needed to optimize these derivatives for clinical application.

In this study, a structurally directed pharmacophore hybridization technique is used to combine the two essential structural scaffolds coumarin and thiazoles in search of a new class of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor for Alzheimer's disease (AD). A library of 120 compounds was designed in two series 5a(1-15), 5b(16-30), 5c(31-45), 5d(46-60), and 6a(61-75), 6b(76-90), 6c(91-105), 6d(106-120) using various substituted phenol, β-ketoesters, and thiazole derivatives. Eleven compounds were identified as potential hybrids using molecular property filter analysis and molecular docking studies, and they comprise N-substituted thiazole coumarin derivatives. The docking results indicated that compounds 5b16 and 5c35 exhibited strong binding interactions with GLY116, GLY117, TYR332, and HIS438 (ranging from -27.42 to -24.18 kcal/mol) and GLY119, ASP72, and PHE288 (ranging from -32.21 to -25.92 kcal/mol) when tested against AChE (1EVE) and BuChE (1P0I) inhibitors. These compounds were synthesized via conventional methods and characterized by different spectroscopic methods. In vitro anti-cholinesterase activity results indicated that two compounds, for example, 5b16 and 5c35 showed potent to moderate activity against AChE and BuChE with IC50 (2.00 ± 0.09-29.63 ± 0.48) µM and (34.93 ± 0.62-17.92 ± 0.42) µM, respectively. Our study demonstrated the development of a novel class of hybrid coumarin thiazole derivatives as AChE and BuChE inhibitors, and these compounds could be utilized against ADs.

The present study demonstrated the design and synthesis of novel 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives as putative inhibitors against various infective diseases. The title analogues were synthesized in a multi-step process, and their structures were verified through elemental analysis and a variety of spectral analyses (FT-IR, 1H NMR, 13C NMR, mass). Compounds 12a was identified as prospective lead compound against HIV-1 based on their high CDdocker interaction energy and stability among the developed derivatives, according to molecular docking and MD simulation experiments with HIV-1 RT. Compound 12a was found effective against HIV-1 in a cell-based experiment, preventing the virus from replicating in CEM-GFP cells infected with 0.5 MOI of HIV-1 NL4-1. In the RNA-dependent DNA polymerase (RDDP) activity of the HIV-1 RT enzyme using a cell free based RT assay, compound 12a showed a therapeutic index of 113 and an EC50 of 125.1 nM. All of the compounds inhibited SARS-CoV-2 replication in the VeroE6-GFP cell line to varying degrees; compound 10e, 12e, 12a, 12b, and 12c, in particular, showed considerable inhibitory activity. The compounds exhibited stronger antibacterial action against Gram-negative than Gram-positive bacteria in an antimicrobial assay, and a SAR analysis revealed that tri-substituted 1,3,5-triazine derivatives exhibited greater inhibitory activity than di-substituted ones. Additionally, 12d and 12e were found to be the most effective inhibitors of P. aeruginosa biofilms when tested against this bacterium. The most active inhibitors, 12a and 12e, were also tested for thermodynamic solubility at pH 7.4 via miniaturized shake-flask method. Here, their solubility was found to be significantly influenced by the presence of hydroxyl group and morpholine. In conclusion, our research demonstrated the significant inhibitory activity of 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives against HIV, SARS-CoV-2, and bacterial microorganisms.

In this study, a library of 138 hybrid nicotinamide-substituted 1,3,5-triazine compounds was designed using various heterocyclic moieties. From this library, ten compounds 4A (1, 8, 12, 14, 36, 38), 4B (37, 38), and 4C (21, 22) were selected through in silico screening, which included assessments of molecular properties, ADME profiles, toxicity predictions, and docking studies targeting the active sites of acetylcholinesterase (AChE, PDB ID: 1EVE) and butyrylcholinesterase (BChE, PDB ID: 4TPK). Docking results indicated that compounds 4A36 and 4A38 exhibited strong binding interactions with critical amino acids HIS440, GLY119, SER200, GLY118, ASP72, ASN85, TRP84 for AChE and TRP82, TRP430, TYR128, LEU286, TRP231, ALA328, PHE329 for BChE with binding affinities of -284.72 kcal/mol and -263.98 kcal/mol, respectively, comparable to the standard drug donepezil. The selected compounds were synthesized through conventional methods and characterized using various spectroscopic techniques. In vitro anti-cholinesterase activity evaluations revealed that compound 4A36 exhibited potent inhibition against AChE with IC50 value of 1.77 +/- 0.15 mu M and compound 4A38 exhibited moderate inhibition against BChE, with IC50 value of 4.80 +/- 0.62 mu M. These findings suggest that the hybrid scaffolds developed in this study hold significant potential for advancing the design of innovative therapeutic agents to treat Alzheimer's disease and related cognitive disorders.

Malaria parasites have demonstrated a remarkable ability to develop resistance to antimalarial drugs and malaria continues to be a major global health burden, necessitating the urgent development of novel and effective antimalarial agents. In this study, we employed an integrated approach of in silico screening, chemical synthesis, and antimalarial investigation to evaluate PABA-glutamic acid conjugated 1,3,5-triazine hybrids as potential antimalarial candidates. In the initial phase, virtual screening was performed utilizing molecular docking against mutant Plasmodium falciparum dihydrofolate reductase (Pf-DHFR) protein (PDB: 1J3K) followed by molecular dynamics simulation studies for the highest scoring compounds. Compounds for synthesis were selected based on their binding affinities and subsequently synthesized and characterized using various spectroscopic techniques. In the final phase, the in vitro antimalarial activity of the synthesized hybrids was evaluated in chloroquinesensitive Pf-3D7 and chloroquine-resistant Pf-Dd2 strains; with additional cytotoxicity assessments on human fibroblast cell line and in vivo antimalarial screening. The results revealed high binding affinity towards the mutant protein with good stability in molecular docking and molecular dynamics simulation studies. Also, in vitro antimalarial study revealed promising antimalarial properties for all the compounds. Compound L8 with IC50 2.49 mu M in 3D7 & 2.89 mu M in Dd2 was identified as the most promising lead. In conclusion, the integrated approach of in silico screening, chemical synthesis, and antimalarial investigation yielded a series of PABAglutamic acid conjugated 1,3,5-triazine hybrids with significant potential as new antimalarial drug candidates. These findings highlight the importance of rational drug design and computational methodologies in identifying promising compounds, ultimately contributing to the ongoing efforts to combat malaria and improve global health.

Background: Since their inception, preclinical experimental models have played an important role in investigating and characterizing disease pathogenesis. These in vivo, ex vivo, and in vitro preclinical tests also aid in identifying targets, evaluating potential therapeutic drugs, and validating treatment protocols. Introduction: Diarrhea is a leading cause of mortality and morbidity, particularly among children in developing countries, and it represents a huge health-care challenge on a global scale. Due to its chronic manifestations, alternative anti-diarrheal medications must be tested and developed because of the undesirable side effects of currently existing anti-diarrheal drugs. Methods: Several online databases, including Science Direct, PubMed, Web of Science, Google Scholar and Scopus, were used in the literature search. The datasets were searched for entries of studies up to May, 2022. Results: The exhaustive literature study provides a large number of in vivo, in vitro and ex vivo models, which have been used for evaluating the mechanism of the anti-diarrheal effect of drugs in chemically-, pathogen-, disease-induced animal models of diarrhea. The advances and challenges of each model were also addressed in this review. Conclusion: This review encompasses diverse strategies for screening drugs with anti-diarrheal effects and covers a wide range of pathophysiological and molecular mechanisms linked to diarrhea, with a particular emphasis on the challenges of evaluating and predictively validating these experimental models in preclinical studies. This could also help researchers find a new medicine to treat diabetes more effectively and with fewer adverse effects.

Emerging trends have nowadays been involved for the sustainability in Pharmaceutical industry. The concept of Green technology, Green Chemistry are growing attentions as the industries produces a significant amount of wastes and Green house gases with the utilization of large volume of water. The implementation of energy efficient system, using electric vehicles in logistics operations and independent verifications such as leadership in energy, environmental design certifications that focuses on company’s building designs, construction are considered to be resource efficient which minimizes its carbon footprint. In order to minimize the impact on environment in a cost effective manner the designing of the chemical process with reduction in the use and creation of hazardous substances should be incorporated. To achieve sustainability in operational perspectives integration of Green supply chain (GSC) can also be adopted. However, the potential risk and finalizing the risks involved in adopting the GSC initiatives within the pharmaceutical industry depends on fuzzy Delphi approach and fuzzy Analytical Hierarchy process (AHP). According to the data obtained during a survey conducted in top global pharmaceutical companies, the two main obstacles to GC adoption are affairs related to regulatory bodies and pressures to deliver new medications. Hence, it is necessary to apply life cycle assessment metrics, enhance GC education, build effective supplier management programmes, and increase the application of green chemistry throughout the entire supply chain. Large decline in Toxics Release Inventory (TRI) release from the pharmaceutical industry in U.S. have been observed with the adoption of GC as per the reports of researchers. Despite not being publicly disclosed, generic medication companies, API manufacturers, and smaller R&D pharmaceutical businesses show interest in and advancements in GC principles, according to the global pharmaceutical supply chain. The current chapter aims to focus new technologies adoption of GC by pharmaceutical companies and API manufactures, to examine the drivers and barriers to greater adoption of GC by industry and to identify opportunities for wider acceptance of GC by pharma industry and API manufacturers in India.

Malaria is a significant global public health issue, particularly prevalent in Africa, Asia, and Latin America, necessitating urgent research into novel and efficient therapies. In the current research, we have designed pyridine substituted pyrazole 1,3,5-triazine derivatives as antimalarials. A library including 300 compounds, designated as 7S (1–300), has been generated using a variety of aliphatic and aromatic amines. Ten compounds have been selected via in silico screening such as molecular properties, toxicity study, docking study and conventional synthesis for antimalarial evaluation against P. falciparum strains 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant). The docking results of compounds 7s258 and 7s5 revealed higher binding interaction with amino acids Leu46, Phe58, Phe116, Ala16 (-341.33 kcal/mol), Ser111, Ile112, Val45 Pro113, Leu119 (-335.16 kcal/mol) and Phe58, Ser111, Ile112, Phe116 (-354.47 kcal/mol), Phe58, Met55, Leu46, Leu164, Pro113 (-346.34 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors. Further these compounds were synthesized by simple nucleophilic substitution reaction and characterized by different spectroscopic methods. The in vitro antimalarial assay results suggested that these compounds exhibit considerable antimalarial activity with IC50 values of 32.74–46.80 μM and 28.05–54.95 μM against both the chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum, respectively. Among the ten derivatives, compound 7s258 and 7s5 show substantial potential as antimalarial agents. They are highly suitable for further refinement in the field of drug development to effectively decrease the global malarial burden.